Theoretical Study on the Biosynthesis of the Mandapamates: Mechanistic Insights Using Density Functional Theory.

Density functional theory (B3LYP-D3(BJ) and ωB97XD) calculations have been used to assess the stereochemical outcomes of the proposed transannular [4 + 2] cycloaddition pathway for the biosynthesis of mandapamate and isomandapamate from macrocyclic intermediates. Calculations reveal that the topological shift between macrocyclic conformers is vital in controlling the stereoselectivity of the downstream steps toward the isomeric mandapamates. A stepwise 4 + 2 type process is energetically favored over a concerted [4 + 2] pathway at room temperature, and is consistent with the stereochemistries found in the natural products.

Exploring the Dual Functions of Distal Acyl Group Direction in Various Nucleophilic Environments.

A universal glycosylation strategy could significantly simplify glycoside synthesis. One approach to achieving this goal is through acyl group direction for the corresponding 1,2-, 1,3-, 1,4-, or 1,6-trans glycosylation; however, this approach has been challenging for glycosidic bonds that require distal equatorial-acyl group direction. We developed an approach in weakly nucleophilic environments for selective 1,4-trans glycosylation directed by the equatorial-4-O-acyl group. Here, we explored this condition in other distal acyl groups and found that, besides 1,n-trans direction, acyl groups also mediated hydrogen bonding between acyl groups and alcohols. The latter showed a diverse effect and classified the acyl group direction into axial and equatorial categories. Corresponding glycosylation conditions were distinguished as guidance for acyl group direction from either category. Hence, acyl group direction may serve as a general glycosylation strategy.

Multideuteration of Nitroaromatics by Silver-Catalyzed Hydrogen-Isotope Exchange.

Silver-catalyzed deuteration of nitroaromatics has been achieved using D2O as the deuterium source. Distinct from the well-established directing group-guided hydrogen-isotope exchange, this protocol showed an interesting deuteration pattern, where considerable deuterium accumulation was observed around the aromatic rings. Controlling experiments suggested that the deuteration was initiated by a silver-promoted C-H activation. Therefore, a tentative two-stage deuteration mechanism involving aryl-silver species was proposed to explain the deuteration on meta- and para-positions.

Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange.

A practical and scalable ortho-selective deuteration of aromatic aldehydes was accomplished by Pd-catalyzed hydrogen isotope exchange with deuterium oxide as an inexpensive deuterium source. The use of tert-leucine as a transient directing group facilitates the exchange, affording a wide range of ortho-deuterated aromatic aldehydes with deuterium incorporation up to 97%. The control experiments suggest that the addition of silver trifluoroacetate resists the unexpected reduction of Pd(II), while the theoretical study indicates a rapid reversible concerted metalation-deprotonation process.

Synthesis of an isomer of lycoplanine A via cascade cyclization to construct the spiro-N,O-acetal moiety.

An isomer of lycoplanine A with a 6/10/5/5 tetracyclic skeleton was synthesized using D-A reaction and cascasde reaction to respectively construct the [9.2.2] pentadecane skeleton and the challenging 1-oxa-6-azaspiro[4.4]nonane spirocenter. Morever, detailed DFT calculations were conducted to explain the selectivity in the D-A reaction. This study may provide sufficient experience for the total synthesis of lycoplanine A and other alkaloids with similar spiro-N,O-acetal cores.

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1.

A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination (R2) of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules.

C-N and C-O Bond Formation in Copper-Catalyzed/Mediated sp3 C-H Activation: Mechanistic Studies from Experimental and Computational Aspects.

Mechanistic studies on Cu-catalyzed/mediated sp3 C-H amidation and acetoxylation are investigated from experimental and computational aspects. The concerted metalation-deprotonation (CMD) mechanism rather than a radical-involved pathway is proved to occur in amidation and acetoxylation reactions, and this is the rare example of the CMD mechanism involved in the more challenging sp3 C-H activations. Theoretical calculations demonstrated that CMD is the rate-determining step either for methylic or benzylic positions in amidation and acetoxylation reactions, and intermolecular nucleophilic addition of acetate anions is more favorable than the ring opening of ß-lactams and intramolecular acetoxylation. These mechanistic studies on the divergent and condition-dependent product formation are critical for developing Cu-promoted C-H functionalization via the CMD mechanism.

Heliaquanoids A-E, Five Sesquiterpenoid Dimers from Inula helianthus-aquatica.

Heliaquanoid A (1), the first exo-2,4-linked Diels-Alder adduct between a pseudoguaianolide dienophile and a guaianolide diene, and heliaquanoids B-E (2-5), four new 2,4-linked Diels-Alder adducts between a xanthanolide dienophile and a guaianolide diene, were isolated from stems and leaves of Inula helianthus-aquatica. Their structures were determined by NMR spectroscopy, a modified Mosher's method, electronic circular dichroism, and X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 7.5 and 4.9 µM, respectively.

Artificial intelligence for small molecule anticancer drug discovery.

INTRODUCTION: The transition from conventional cytotoxic chemotherapy to targeted cancer therapy with small-molecule anticancer drugs has enhanced treatment outcomes. This approach, which now dominates cancer treatment, has its advantages. Despite the regulatory approval of several targeted molecules for clinical use, challenges such as low response rates and drug resistance still persist. Conventional drug discovery methods are costly and time-consuming, necessitating more efficient approaches. The rise of artificial intelligence (AI) and access to large-scale datasets have revolutionized the field of small-molecule cancer drug discovery. Machine learning (ML), particularly deep learning (DL) techniques, enables the rapid identification and development of novel anticancer agents by analyzing vast amounts of genomic, proteomic, and imaging data to uncover hidden patterns and relationships. AREA COVERED: In this review, the authors explore the important landmarks in the history of AI-driven drug discovery. They also highlight various applications in small-molecule cancer drug discovery, outline the challenges faced, and provide insights for future research. EXPERT OPINION: The advent of big data has allowed AI to penetrate and enable innovations in almost every stage of medicine discovery, transforming the landscape of oncology research through the development of state-of-the-art algorithms and models. Despite challenges in data quality, model interpretability, and technical limitations, advancements promise breakthroughs in personalized and precision oncology, revolutionizing future cancer management.

Strategies for utilizing covalent organic frameworks as host materials for the integration and delivery of bioactives.

Covalent organic frameworks (COFs), a new and developing class of porous framework materials, are considered a type of promising carrier for the integration and delivery of bioactives, which have diverse fascinating merits, such as a large specific surface area, designable and specific porosity, stable and orderly framework structure, and various active sites. However, owing to the significant differences among bioactives (including drugs, proteins, nucleic acid, and exosomes), such as size, structure, and physicochemical properties, the interaction between COFs and bioactives also varies. In this review, we firstly summarize three strategies for the construction of single or hybrid COF-based matrices for the delivery of cargos, including encapsulation, covalent binding, and coordination bonding. Besides, their smart response release behaviors are also categorized. Subsequently, the applications of cargo@COF biocomposites in biomedicine are comprehensively summarized, including tumor therapy, central nervous system (CNS) modulation, biomarker analysis, bioimaging, and anti-bacterial therapy. Finally, the challenges and opportunities in this field are briefly discussed.

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones.

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides.

Palladium-Catalyzed Decarbonylative Michaelis-Arbuzov Reaction of Carboxylic Acids and Triaryl Phosphites.

A Pd-catalyzed decarbonylative Michaelis-Arbuzov reaction of carboxylic acids and triaryl phosphites for preparing aryl phosphonates under anhydride-free conditions has been reported. In this context, triaryl phosphites serve as both reagents for activating the carboxylic acids and substrates for the reaction. There have been no reports to date of efficient and direct methods for the in situ activation of carboxylic acids using triaryl phosphites. In comparison to known methods, this reaction avoids the use of organohalides and has an excellent functional group tolerance for the synthesis of various aryl phosphonates from triaryl phosphites and carboxylic acids. This reaction is scalable and applicable to the synthesis of aryl phosphonates featuring bioactive fragments.

Discovery of novel SOS1 inhibitors using machine learning.

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 µg mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFß1R1 inhibitor.

The transforming growth factor ß1 (TGFß1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-ß1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

Nucleation Regulation and Mesoscopic Dielectric Screening in α-FAPbI3.

While significant advancements in power conversion efficiencies (PCEs) of α-FAPbI3perovskite solar cells (PSCs) have been made, attaining controllable perovskite crystallization is still a considerable hurdle. This challenge stems from the initial formation of δ-FAPbI3, a more energetically stable phase than the desired black α-phase, during film deposition. This disrupts the heterogeneous nucleation of α-FAPbI3, causing the formation of mixed phases and defects. To this end, polarity engineering using molecular additives, specifically ((methyl-sulfonyl)phenyl)ethylamines (MSPEs) are introduced. The findings reveal that the interaction of PbI2-MSPEs-FAI intermediates is enhanced with the increased polarity of MSPEs, which in turn expedites the nucleation of α-FAPbI3. This leads to the development of high-quality α-FAPbI3 films, characterized by vertical crystal orientation and reduced residual stresses. Additionally, the increased dipole moment of MSPE at perovskite grain boundaries attenuates Coulomb attractions among charged defects and screens carrier capture process, thereby diminishing non-radiative recombination. Utilizing these mechanisms, PSCs treated with highly polar 2-(4-MSPE) achieve an impressive PCE of 25.2% in small-area devices and 20.5% in large-area perovskite solar modules (PSMs) with an active area of 70 cm2. These results demonstrate the effectiveness of this strategy in achieving controllable crystallization of α-FAPbI3, paving the way for scalable-production of high-efficiency PSMs.

ß-l-Rhamnosylation and ß-d-Mannosylation Mediated by 4-O-Ester Groups in a Weakly Nucleophilic Environment.

eq-4-O-Acyl group directed ß-rhamnosylation and ß-mannosylation are achieved in a carborane or BARF anion formed weakly nucleophilic environment with the assistance of a 2,3-orthocarbonate group. The 4-O-acyl group plays a critical role in directing the ß-selectivity, and the weakly coordinating anion is essential to amplify this direction. The orthocarbonate group could be readily removed with 1,3-propanediol in the presence of BF3·Et2O.

Regioselective Cycloaddition and Substitution Reaction of Tertiary Propargylic Alcohols and Heteroareneboronic Acids via Acid Catalysis.

We report an acid-catalyzed formal cycloaddition and dehydrative substitution reaction of tertiary propargylic alcohols and heteroareneboronic acids. The properties of the substituents on the alkynyl moiety determines the regioselectivity of the reaction, which could selectively construct fused heterocycles, tetrasubstituted allenes, or 1,3-dienes. This reaction proceeds efficiently with a wide array of substrate scope in up to 89% yield. A significant advantage of this protocol is the transition-metal-free and mild conditions needed.

Potassium tert-butoxide promoted regioselective deuteration of pyridines.

A regioselective deuteration at the ß- and γ-position of pyridines is reported. Efficient deuteration occurred with a combination of KOtBu and DMSO-d6, replenishing the prevailing α-deuteration of the pyridine systems. Preliminary mechanistic studies suggested that the dimsyl carbanion acts as one of the key intermediates.